Endothelin-I (ET) is a 21-amino acid vasoconstrictive peptide isolated from endothelial cell culture in 1987. We have found that ET elicits a robust (10-fold) increase of phosphoinositide hydrolysis in cerebellar granule cells (an EC50 of about 2 nM). This is a receptor-mediated activity and strictly calcium dependent; however, the calcium dependence does not involve the activation of L-type voltage-sensitive calcium channel or Na+/Ca2+ exchange. Prestimulation of granule cells results in an extremely rapid homologous desensitization of the phosphoinositide response. ET also induces the release of preloaded 3H-D-aspartate, a marker of endogenous glutamate, from granule cells. Detailed biochemical and pharmacological characterizations reveal that the ET-induced transmitter release may not be entirely due to the action on phosphoinositide breakdown, suggesting other signal transduction mechanisms mediated by ET receptors in neurons. our preliminary evidence indicates that cerebellar granule cells synthesize and release ET. Taken together, these results support the notion that ET is a neuropeptide. Very recently, we showed that primary cultures of cerebellar astrocyte and C6-glioma cells also express ET receptors coupled to phospholipase C. However, distinct forms of G-proteins are involved in the coupling of this lipase to glial and neuronal ET receptors. ET-induced inositol phosphate formation is potentiated by calcium ionophores and associated with a 4-fold increase in intracellular calcium (Ca2+]i. This [Ca2+]i increase is largely dependent on extracellular calcium but insensitive to calcium channel blockers such as verapamil and dihydropyridines. Cd2+, La3+, and Mn2+ can partially block the ET-induced increase of [Ca2+]i. Prestimulation of ET desensitizes the [Ca2+]i increase induced by ET, but not that induced by ATP. The physiological role of ET-induced phosphoinositide turnover and calcium mobilization in cells of glial origin are being explored.